Dissemination of cells from the primary tumor in the form of metastasis in distant organs is responsible for 90% of the cancer-related deaths, representing over 500,000 people dying every year in the United States alone. Consequently, metastases are among the most important biological problem to address in the area of cancer research. Although a cellular link between the primary malignant tumor and the peripheral metastases has been established in the form of circulating tumor cells (CTCs) in peripheral blood, a major challenge remains in deciphering the biology of this very unique cellular population, and ultimately, improving our systems level understanding of "how cancer spreads and kills". This is especially true for lung cancer, the leading cause of cancer deaths in the United States and will be the primary focus of our proposal for the Quantum Project. Given that more than 85% of major cancers, including lung cancer, originate from their epithelial cells, our focus will be the epithelial CTCs present in peripheral blood of the patients with metastatic lung cancer. However, we need to overcome a "high-risk" and critical unmet technological challenge, namely cell sorting technology for efficient isolation of CTCs with frequencies as low as 1 in 10e9 in whole blood. To address this unmet technological challenge, we plan to develop a new point-of-care, disposable microchip technology capable of selective separation of rare CTCs at a rate of 1 to 10 million cells per second, and to ultimately introduce microfluidic technologies to clinical cancer medicine (Overall Goal). Human studies will be given priority and will provide rigorous test of our technological innovations. This is a philosophical decision in that the team of investigators involved in this project strongly believe that the vision of the Quantum Project, namely, solving or profoundly improving a specific health condition using technology-driven approaches in a time period of 8 to 10 year must have a sharp focus on real systems at the onset of the program. Much progress has occurred in cancer biology using mouse and other animal models, but it is also recognized that there are significant limits to this mimicry (How). This point-of-care microchip blood biopsy has the potential to transform lung cancer patient care through early molecular diagnosis of lung cancer, the identification of new biomarkers to predict outcomes both good and bad in cancer, and finally, suggest new targets for further basic and clinical research, as well as fruitful targets for pharmacological interventions and immunotherapy in cancer (Future Benefits).